Type 2 diabetes, a heterogeneous disorder of polygenic origin, is associated with defects in beta cell function and insulin action. While the nature of the beta cell defect has yet to be determined, chronic oxidative stress resulting from elevated plasma levels of glucose and lipids appears to be an important factor in the loss of beta cell mass during diabetes development. Mitochondrial DNA (mtDNA) is uniquely sensitive to oxidative stress, and increased levels of mtDNA mutations (>20-30%) are associated with diabetes development in patients with mitochondria! disease;however, a much greater impact on the etiology of Type 2 diabetes may arise from the somatic accumulation of random mtDNA mutations (levels 0.01- 0.1 %) that occurs with age in nearly all individuals. The contribution of mutations at these levels to the development of diabetes is unknown. The broad goal of this research is to test the hypothesis that increased levels of random mutations in beta cell mtDNA lead to the loss of beta-cell function and the inability to maintain normal glycemic control. Specific aims are to elucidate the physiological impact of rising levels of mtDNA mutations in beta cells and to confirm that transgene toxicity does not contribute to diabetes development.